Acquired Immune Deficiency Syndrome (AIDS) is believed to be caused by the Human Immunodeficiency Virus (HIV) family of retroviruses. The retrovirus attacks and ultimately destroys the host's cell-mediated immune system. In the human cell-mediated immune system, T cells and macrophages are key to recognition of infectious agents. T cells have surface receptors that recognize either the combination of "processed" (i.e., partially digested) antigen with histocompatibility markers on antigen-presenting cells or the combination of unprocessed "superantigens" with part of the histocompatibility marker on the antigen presenting cells. T cells interact with and cause macrophages to engulf and destroy a recognized infectious agent. Both T cells and macrophages have T4 (or CD4) receptors on their surfaces. It is known that HIV infects a cell by binding to T4 receptor after which it enters the cell by endocytosis. The HIV genome is then transcribed to DNA by its own by its own reverse transcriptase (RT), and integrated into the host cell genome. Replication of the virus in the cell ultimately destroys the cell.
During the HIV latency period, which can extend many years, the host's helper T4 lymphocytes die off, rendering the host increasingly susceptible to various bacterial and other infections. Infected lymphocytes secrete an oncoprotein, which drives tumorigenesis/angiogenesis in AIDS-associated Kaposi's sarcoma (KS).
In addition to symptoms arising from immunodeficiency, patients with AIDS show neuropsychological defects. Eventually AIDS-associated damage to the brain and the central nervous system also occurs. The central nervous and immune systems share a large number of specific cell-surface recognition molecules which serve as receptors for neuropeptide-mediated intercellular communication. In particular, the central nervous system has CD4 cell-surface recognition molecules.
HIV attachment to the T4 (CD4) receptor occurs via the viral coat protein gp120. This protein has also been shown to affix covalently to cells of the immune system as well as to the brain membranes of humans, rats, and monkeys. A portion of gp120, an octapeptide called peptide T, binds to the T4 receptor in vitro and block attachment of the virus to the CD4 receptors of T cells, monocytes and cells of the central nervous system that express CD4 receptor. Peptide T has high affinity for CD4 receptors of T cells and monocytes with dissociation constants in the low nanomolar range. See, Pert et al. (1986) Proc. Natl. Acad. Sci. USA 83, 9254-9258; Ruff et al. (1987a) FEBS Lett., 211:17-22; Ruff et al. (1987b) Lancet September 26:751. Several peptides from the coat proteins of other viruses also exhibit high affinity for binding to CD4. See, Ruff et al. (1987a) and Ruff et al. (1987b).
In several clinical protocol trials for patients with AIDS, peptide T was reported to effect significant amelioration of AIDS symptoms, including AIDS-related dementias. Buzy et al. (1992) Brain Research 598: 10-18. The effect in AIDS-related dementias may result from blocking HIV attack on the CD4 positive cells of the central nervous system. Peptide T also protects against gp120 protein induced neuronal death. Benneman et al. (1988) Drug Dev. Res. 15(4): 361-370.
One problem with the use of peptide T in the treatment of AIDS is its short half-life (10-60 minutes) which greatly reduces its efficacy. Ruff et al. (1991) Prog. Neuro-Pyschopharmacol. & Biol. Psychiat. 15: 791-799.
One of the few agents reported useful clinically for HIV is AZT, 3'-azido-3'-deoxythymidine, a nucleoside chain terminator in transcription. However, the clinical benefits of AZT have not yet been definitively established. AZT induces drug resistance by mutating the HIV Reverse Transcriptase (RT) and it is severely toxic to the host. Current practice, also as yet without proven efficacy, employs a combination therapy using mixed nucleosides at lower doses.
A number of compounds have been reported to inhibit HIV activity or replication, including HPA-23, interferons, ribavirin, phosphonoformate, ansamycin, suramin, imuthiol, penicillamine, rifabutin, AL-721, 2',3'-dideoxycytidine (DDC), 2',3'-dideoxyadenosine (DDA), 3'-azido-2',3'-dideoxyuridine (AzddU),2',3'-didehydrocytidine, 3'-deoxy-2',3'-didehydrothymidine and 3'-azido-5-ethyl-2',3'-dideoxyuridine (AzddEU). While each of these compounds may have a place in the therapeutic regimen for AIDS patients, none are wholly effective in blocking HIV infection, reversal of symptoms, or major amelioration of the disease course. Many of these agents are significantly toxic and produce major side effects which limit their utility.
Recently, diazepines have been reported active against HIV RT and Trans-Activator Gene Protein (Tat). Cornell, E. et al. 33rd Interscience Conference on Antimicrobral Agents and Chemotherapy, New Orleans, La., Oct. 17-20, 1993 (Program and Abstracts); Ayuso, J. L. (1994) Drugs 47(4): 599-610. Inhibitors of the HIV protease have also been developed. See: Abdel-Meguid, S. S. et al. (1994) Biochemistry 33(39): 11671-11677; Dorsey, B. D. et al. J. Medicinal Chem. (1994) Bioorg. Med. Chem. Letts. 4(19): 2343-2346; Kim et al. (1994) Bioorg. Med. Chem. Letts. 4(19): 2273-2278.
There remains a great need for alternative agents, particularly non-nucleoside and non-peptide drugs, which will effectively inhibit HIV activity and replication and yet produce fewer undesired side effects. Of particular, interest in view of the inhibitory activity of peptide T are non-peptide agents which mimic its binding affinity for T4 (CD4) receptors.